Oxopyrrolidine compounds, preparation of said compounds and their use in the manufacturing of levetiracetam and analogues

ABSTRACT

The present invention relates to an improved process for the preparation of (S)-(-)-α-ethyl-2-oxo-1-pyrrolidine acetamide and analogues thereof. The invention also relates to compounds of the general formula (6)  
                 
 
wherein R 1  is methyl or ethyl; and R 2  is C 2 -C 4  alkyl, C 2 -C 4  alkenyl or C 2 -C 4  alkynyl, optionally substituted by one or more halogen, and their preparation processes.

This invention concerns a new and improved process for the preparationof (S)-(-)-α-ethyl-2-oxo-1-pyrrolidine acetamide and analogues thereof,which is referred to under the International Non-proprietary Name ofLevetiracetam. Levetiracetam is known as a useful therapeutic agent forthe treatment or prevention of epilepsy and other neurologicaldisorders. This invention also discloses novel intermediates and theiruse in manufacturing processes of Levetiracetam and analogues thereof.

Levetiracetam or (S)-(-)-α-ethyl-2-oxo-1-pyrrolidine acetamide, alaevorotatory compound is disclosed as a protective agent for thetreatment and the prevention of hypoxic and ischemic type aggressions ofthe central nervous system in the European patent No. EP 0 162 036 B andhas the following formula.

This compound is also effective in the treatment of epilepsy, atherapeutic indication for which it has been demonstrated that itsdextrorotatory enantiomer (R)-(-)-α-ethyl-2-oxo-1-pyrrolidine acetamidecompletely lacks activity (A. J. Gower et al., Eur. J. Pharmacol., 222,1992, 193-203). A process for the preparation of this dextrorotatoryenantiomer has been described in the European patent No. 0165 919.

Manufacturing processes for Levetiracetam have been described in boththe European patent No. 0162 036 and in the British patent No. 2 225322. In the British patent No. 2 225 322(S)-(-)-α-ethyl-2-oxo-1-pyrrolidine acetamide is prepared byhydrogenolysis of(S)-α-[2-(methylthio)ethyl]-2-oxo-1-pyrolidineacetamide in the presenceof a desulfurizing reagent such as NaBH₄/NiCl₂.6H₂O, Raney nickel W-2or, preferably, Raney nickel T-1. However, this process cannot beconveniently applied on an industrial scale for safety and environmentalreasons.

Another industrially applicable process was developed and disclosed in amore recent patent application PCT/EPO1/01956. The process described insaid patent application PCT/EP01/01956 is illustrated in Scheme 1 below.This process is based on the asymmetric hydrogenation of a compound offormula (1), resulting in Levetiracetam (compound of formula (2)). Saidpatent application also describes the efficient asymmetric hydrogenationof related compounds of general formula (3), providing the acid andesters of general formula (4).

Me represents methyl, and Et represents ethyl.

However, it may be desired to convert the ester (4) directly toLevetiracetam (2) by ammonolysis. A disadvantage of performing saidammonolysis is that racemisation may occur, resulting in the formationof the compound of formula (5) as described in Scheme 2. below.

Moreover, the reaction time necessary to obtain a reasonable conversionis generally very long. The reaction time may be decreased by increasingthe reaction temperature, but then the extent of racemisation increasesto unacceptable levels. No compromise had until now been found betweenthe reaction time, the temperature and extent of racemisation.

It Is clear that an industrially viable process without theabove-mentioned disadvantage would be extremely desirable.

The process of the present invention largely overcomes the majordisadvantages such as the racemisation discussed above and excessivehydrolysis. In addition, the present invention describes novelintermediates and their use in processes for the preparation ofLevetiracetam and analogues thereof. The invention also relates to newprocesses for preparing said intermediates.

According to a first aspect, the present invention relates to a compoundof formula (6):

wherein R¹ is methyl or ethyl and R² is C₂-C₄ alkyl, C₂-C₄ alkenyl orC₂-C₄ alkynyl, optionally substituted by one or more halogen, preferablyF, Cl, Br or I; as well as the stereoisomers and mixtures thereof.

This invention relates to all stereoisomeric forms such as geometricaland optical enantiomeric and diastereoisomeric forms of the compounds offormula (6) and mixtures (including racemates) thereof. The compounds offormula (6) and some of their intermediates have at least onestereogenic center in their structure, being the carbon atom attached tothe nitrogen atom of the pyrrolidine heterocycle. This stereogeniccenter is indicated in formula (6) by an asterisk (*). This stereogeniccenter may be present in a R or a S configuration, said R and S notationis used in accordance with the rules described in Pure Appl. Chem., 45(1976) 11-30. The compounds of formula (6) have at least a secondstereogenic center in their structure, being the carbon atom of thepyrrolidine cycle to which the R² substituent is attached. Thisstereogenic center may be in a S or a R configuration. Furthermorecertain compounds of formula (6) which contain alkenyl groups may existas Z or E isomers. In each instance, the invention includes bothmixtures and separate individual isomers.

The compound of the formula (6) can be in the form of a solvate, whichis included within the scope of the present invention. The solvates arefor example hydrates, alcoholates and the like. The compound of theformula (6) can also be in the form of a salt, especially apharmaceutical acceptable salt, which are also included within the scopeof the present invention.

According to a preferred embodiment, the present invention relates tothe compound of the general formula (6), wherein the R² substituent ispresent at position 4 on the ring structure, as given in the followinggeneral formula (7) wherein R¹ and R² are as noted above.

According to another preferred embodiment, the present invention relatesto the compound of formula (7), wherein the R² is a C2-C4 alkyl, C2-C4alkenyl or C2-C4 alkynyl, optionally substituted by one or more halogen.

The term alkyl as used herein includes saturated monovalent hydrocarbonradicals having straight, branched or cyclic moieties or combinationsthereof.

The term alkenyl as used herein includes both branched and unbranchedunsaturated hydrocarbon radicals having at least one double bond.

The term alkynyl as used herein includes both branched and unbranchedhydrocarbon radicals having at least one triple bond.

According to a more preferred embodiment, the invention relates to thecompound of the general formula (7), wherein R¹ is methyl and R² ispropyl according to the following formula:

According to yet another more preferred embodiment, the inventionrelates to the compound of the general formula (7), wherein R¹ is methyland R² is 2,2-difluorovinyl according to the following formula:

According to yet another more preferred embodiment, the inventionrelates to the compound of the general formula (7), wherein R¹ is ethyland R² is propyl according to the following formula:

According to yet another more preferred embodiment, the inventionrelates to the compound of the general formula (7), wherein R¹ is ethyland R² is 2,2-difluorovinyl according to the following formula:

According to yet another more preferred embodiment, the inventionrelates to the compound of the general formula (7), wherein R¹ is methyland R² is 2-fluoro-2-methylpropyl according to the following formula:

According to yet another more preferred embodiment, the inventionrelates to the compound of the general formula (7), wherein R¹ is ethyland R² is 2-fluoro-2-methylpropyl according to the following formula:

According to yet another more preferred embodiment, the inventionrelates to the compound of the general formula (7), wherein R¹ is methyland R² is 2,2-difluoropropyl according to the following formula:

According to yet another more preferred embodiment, the inventionrelates to the compound of the general formula (7), wherein R¹ is ethyland R² is 2,2-difluoropropyl according to the following formula:

According to yet another more preferred embodiment, the inventionrelates to the compound of the general formula (7), wherein R¹ is methyland R² is cyclopropylmethyl according to the following formula:

According to yet another more preferred embodiment, the inventionrelates to the compound of the general formula (7), wherein R¹ is ethyland R² is cyclopropylmethyl according to the following formula:

According to yet another more preferred embodiment, the inventionrelates to the compound of the general formula (7), wherein R¹ is methyland R² is 2,2,2-trifluoroethyl according to the following formula:

According to yet another more preferred embodiment, the inventionrelates to the compound of the general formula (7), wherein R¹ is ethyland R² is 2,2,2-trifluoroethyl according to the following formula:

According to another preferred embodiment, the compound of generalformula (6) or (7) is the S isomer as illustrated in the followingformula (8) wherein R¹ and R² are as noted above.

In this preferred embodiment the compounds of formula (8) includecompounds wherein the second stereogenic center, that is the carbon atomof the pyrrolidine heterocycle to which the R² substituent is attached,is in a S or in a R configuration and their mixtures. Furthermorecertain compounds of formula (8) which contain alkenyl groups may existas Z or E isomers. In each instance, the invention includes bothmixtures and separate individual isomers.

The invention also relates to new processes for the manufacture of saidcompound of the general formula (6) as defined above.

According to a first process, named the “Late Ring-Closure route or LRCroute”, said compound of general formula (6) of the invention as definedabove may be manufactured by a process comprising following steps:(a) reaction of a compound of formula (9)

with an alcohol of formula R¹OH wherein R¹ is defined as above,(b) reaction of the corresponding compound of formula (10) thus obtained

with a R²-substituted-ethyl-4-bromobutyrate wherein R² is defined asabove,(c) cyclisation of the corresponding compound of formula (11) thusobtained

with a catalyst, and(d) isolation of the resulting compound.

In this process, the compound of formula (9) is an enantiomerically pureor an enantiomerically enriched compound, the chiral centre (eitherconfiguration) being denoted by an asterisk (*). By enantiomericallyenriched compound is meant a compound containing more than 50%,preferably more than 55%, most preferably more than 60%, of one of theenantiomers. By enantiomerically pure compound is meant a compoundcontaining at least 90%, preferably at least 95%, most preferably atleast 98%, of one of the enantiomers.

The first step (step a) of this first process is preferably effectuatedin the presence of an alcohol (for instance methanol or ethanol) andthionyl chloride. The second step (step b) is the mono-N-alkylation ofthe amino-ester of formula (10) with a R²-substituted ethyl4-bromobutyrate (4-EBB) and is preferably effectuated in the presence ofan alcohol (for instance methanol, ethanol or isopropanol). The alcoholis preferably isopropanol. The use of isopropanol resulted in a majoramount of the monoalkylated ester (11) and a small amount of adialkylated product which may be separated by column chromatography.Alternatively, the monoalkylated product may be precipitated as itshydrochloride salt by means of gaseous HCl. The hydrochloride of themono-alkylated product (solid) is next neutralised with aqueous sodiumcarbonate and extracted with an organic solvent. The second step ispreferably performed in the presence of base, most preferably sodiumcarbonate. The catalyst used in the third step (step c) in the firstprocess is preferably 2-pyridinol. This reaction is non-racemising andprovides enantiomerically enriched or pure (S)-isomers of compounds offormula (8) in the case where the (S) enantiomer of compound (9) is usedas starting material.

According to an alternative process, said compound of general formula(6) of the invention as defined above may be manufactured by a processcomprising the step of cyclisation of the compound of formula (11),wherein R¹ and R² are as defined above. This process is carried outaccording to Scheme 4. below:

According to a second process, said compounds of formula (6) of theinvention as defined above may also be manufactured by a processcomprising following steps:(a) reaction of an α-ketocarboxylic acid derivative of formula (12)

wherein R¹ is as defined above, with a pyrrolidinone of formula (13)

wherein R² is as defined above,(b) reaction of the corresponding compound of formula (14) thus obtained

with hydrogen in the presence of an asymmetric hydrogenation catalyst,and(c) isolation the resulting compound.

This process has as a major advantage that it is much more rapid,simpler, and comprising fewer steps than the first ‘LRC’ route asdiscussed above. All details of this process are disclosed in theapplication PCT/EP01/01956 where it is described for compounds of a moregeneral formula. Said application is hereby further incorporated byreference.

According to a third process, said compounds of the general formula (6)of the invention as defined above may also be manufactured by a processcomprising following steps:(a) reaction of a compound of formula (15)

wherein R^(1′) is C₁-C₆ alkyl and X is Cl, Br, I, alkylsulphonate orsulfate; with a pyrrolidone of general formula (13).

wherein R² is as noted as above;(b) reaction of the corresponding compound of formula (16) thus obtained

with ethyl-X, wherein X is Cl, Br, I, alkylsulphonate or sulfate and anasymmetric alkylation catalyst or additive;(c) optionally, when R^(1′) is different from R¹, reaction of thecompound obtained from step (b) with an alcohol of formula R¹OH, and(d) isolating the resulting compound of formula (6).

According to this third process, R^(1′) is preferably C3-C4 alkyl,especially terbutyl.

According to this third process, the asymmetric alkylation catalyst oradditive is preferably a chiral amine, most preferably selected from(S)-1-(2-pyrrolidinylmethyl)-pyrrolidine (17),(R)-2-methoxyethoxyethyl-1-phenyl-2-piperidinoethylamine (18) and(S)-1-methyl-2-anilinomethyl pyrrolidine (19).

Step (b) of this third process is preferably performed in the presenceof a base (such as mineral, organic or organometallic bases). The baseis preferably butyllithium.

Step (c) of this process is preferably acid or base catalysed.

This process has the advantage that it comprises only few reactionsteps. Another advantage is that it may be performed using inexpensiveand readily available raw materials.

According to a fourth process, the compound of the general formula (6)as defined above may also be prepared by a process comprising followingsteps:(a) reaction of a compound of general formula (20)

wherein R¹ is as defined above, with a pyrrolidone of general formula(13) wherein R² is defined as above;(b) separation of the corresponding compound of general formula (21)thus obtained

wherein R¹ and R² are defined as above;(c) isolation of the resulting compound of general formula (6).

According to this fourth process, the compound of the general formula(6) as defined above may be isolated by industrial chiralchromatographic separation (batch, MCC (Multi Column Chromatography) orSMB (simulated moving bed)) of a compound of general formula (21)according to Scheme 7. below.

The chromatographic process can be carried out using either the batch orMCC process. Each enantiomer can be separated using a chiral stationaryphase to yield enantiomerically pure products.

Commercially available chromatographic columns are for example sold byDAICEL Company or SHISEIDO Company. The preferred DAICEL columns such asthe columns sold under the trademark CHIRALPAK AD, CHIRALPAK AS andCHIRALPAK OD were found to be efficient to this end when mobile phasessuch as mixtures of alkanes with alcohols were used or even a purealcohol or mixtures of alcohols. The alkane or mixtures of alkanesparticularly referred to are: hexane, isohexane or heptane. The alcoholor mixtures of alcohols particularly referred to are: propanol,isopropanol, ethanol or methanol. There is a preference for the use ofheptane among the alkanes and there is a preference for the use ofethanol and methanol among the alcohols. There is a preference for thefollowing mixtures: 50% to 95% for the alkane and 50% to 5% foralcohol(s), or 100% of alcohol.

The preferred SHISEIDO columns such as the columns sold under thetrademark CERAMOSPHER CHIRAL RU-2 or CERAMOSPHER CHIRAL RU-1 were foundto be efficient for the separation when alcohols were used as mobilephase. The alcohols referred to are: propanol, isopropanol, ethanol ormethanol. There is a preference for the use of ethanol and methanolamong the alcohols.

The extrapolation of small-scale batch separations of this type to anindustrial scale proceeds without difficulty in either batch orcontinuous mode.

According to a second aspect, the present invention also relates to aprocess for the manufacture of a compound of the general formula (22′)wherein R^(2′) is hydrogen, C₁-C₄ alkyl, C₂-C₄ alkenyl or C₂-C₄ alkynyl,optionally substituted by one or more halogen, said process comprisingthe ammonolysis of the corresponding compound of formula (6′)

wherein R^(1′) is C₁-C₆ alkyl and R^(2′) is hydrogen, C₁-C₄ alkyl, C₂-C₄alkenyl or C₂-C₄ alkynyl, optionally substituted by one or more halogen,in the presence of water.

Surprisingly, it has been found that performing said ammonolysis in thepresence of water greatly overcomes the disadvantages such asracemisation as described in the background art, and encountered whenusing an organic solvent (e.g. methanol). Other advantage of thisinvention Is minimisation of potential hydrolytic side-reaction.

According to a preferred embodiment, said ammonolysis as described aboveis performed in a mixture of water and an alcohol. Preferred alcoholsare methanol, ethanol, isopropanol and butanol. Most preferably amixture of water and methanol is used. Using a mixture of water and analcohol, especially methanol, offers the additional advantage that thelevel of hydrolysis is even more decreased.

According to a preferred embodiment, said ammonolysis of the inventionas described above is performed with NH_(3.) Preferably, a 10-95% (w/w)NH₃ solution in water is used. Most preferably, a 30-80% (w/w) NH₃solution in water, especially a 50% NH₃ solution in water, is used.

According to yet another preferred embodiment, said ammonolysis of theinvention as described above is performed at 0 to 40° C., mostpreferably at a temperature of 0 to 25° C., especially at a temperatureof about 3 to 10° C.

In the process according to the invention, the molar ratio of NH₃ to thecompound of formula (6′) is generally at least 1, preferably at least 4,most preferably at least 6. The molar ratio does preferably not exceed100.

According to a preferred embodiment of the process for the manufactureof the compound of formula (22′), a compound of the general formula (6′)is used wherein R^(1′) is methyl, ethyl or a C₃-C₄ alkyl. Especiallypreferred are compounds of general formula (6′) wherein R^(1′) is methylor ethyl and most preferably wherein R^(1′) is methyl.

According to another preferred embodiment of the process for themanufacture of the compound of formula (22′), a compound of the generalformula (6′) is used wherein R^(2′) is hydrogen.

According to a more preferred embodiment of the process for themanufacture of the compound of formula (22′) a compound of the generalformula (6′) is used wherein R^(1′) is methyl and R^(2′) is hydrogenaccording to the following formula:

The above compound is referred to as PBM (methyl2-(2-oxo-pyrrolidin-1-yl) butyrate).

According to yet another embodiment of the process for the manufactureof the compound of formula (22′), a compound of the general formula (6′)is used wherein R^(1′) is ethyl and R^(2′) is hydrogen according to thefollowing formula:

The above compound is referred to as PBE (ethyl2-(2-oxo-pyrrolidin-1-yl) butyrate).

According to yet another embodiment of the process for the manufactureof the compound of formula (22′), a compound of the general formula (6′)is used wherein the R^(2′) substituent is present at position 4 on thering structure, as given in the following general formula (7′) whereinR^(1′) and R^(2′) are as noted above.

According to another preferred embodiment of the process according tothe invention, the compound of formula (6′) is the S isomer asillustrated in the following formula (8′) wherein R^(1′) and R^(2′) areas noted above.

The use of an S isomer of formula (8′) in the process according to theinvention permits to obtain compounds of formula (22′) being S isomers.Compounds of formula (6′) wherein R^(2′) is different from hydrogenpossess a second stereogenic center, being the carbon atom of thepyrrolidine ring to which the R^(2′) substituent is attached. In thiscase, this stereogenic center may be in an S- or R-form or mixtures ofboth forms may be used.

According to a more preferred embodiment of the process for themanufacture of the compound of formula (22′), a compound of the generalformula (6′), (7′) or (8′) is used, wherein R^(2′) is selected from thegroup of hydrogen, propyl, 2,2-difluorvinyl, 2-fluoro-2-methylpropyl,2,2-difluoropropyl, cyclopropylmethyl and 2,2,2-trifluoroethyl.

The ammonolysis process according to the invention permits highconversion rates. The ammonolysis process according to the inventionoffers also the advantage that the amount of racemisation and hydrolysisis very low, even negligible. A simple crystallisation of the crudeproducts from this ammonolysis in an organic solvent may give purecompounds, such as pure Levetiracetam.

The compound of formula (6′) used as starting material in the processfor the manufacture of a compound of formula (22′), can be manufacturedby any process suitable therefore.

According to a first variant, the compound of formula (6′) ismanufactured by a first new process comprising following steps:(a) reaction of a compound of formula (9)

with an alcohol of formula R^(1′) OH wherein R^(1′) is defined as above.(b) reaction of the corresponding compound of formula (10′) thusobtained

with a R^(2′)-substituted-ethyl-4-bromobutyrate wherein R^(2′) isdefined as above,(c) cyclisation of the corresponding compound of formula (11′) thusobtained

in the presence of a catalyst, and(d) isolation of the resulting compound.

In this process, the compound of formula (9) is an enantiomericallyenriched or an enantiomerically pure compound, the chiral centre (eitherconfiguration) being denoted by an asterisk (*).

This first new process as such for the manufacture of a compound offormula (6′) is another aspect of the present invention.

The first step (step a) of this process is preferably performed in thepresence of an alcohol (for instance methanol or ethanol) and thionylchloride. The second step (step b) of this process is themono-N-alkylation of the amino-ester of formula (10′) with aR^(2′)-substituted ethyl 4-bromobutyrate (4-EBB) and is preferablyperformed in the presence of an alcohol (for instance methanol, ethanolor isopropanol). The alcohol is preferably isopropanol. The use ofisopropanol presents the further advantage that transesterification didnot occur. Moreover, the use of isopropanol resulted in a major amountof the monoalkylated ester (11′) and only a small amount of adialkylated product which may be separated by column chromatography.Alternatively, the monoalkylated product may be precipitated as itshydrochloride salt by means of gaseous HCl. The hydrochloride of themono-alkylated product (solid) is next neutralised with aqueous sodiumcarbonate and extracted with an organic solvent. The second step ispreferably performed in the presence of base, preferably sodiumcarbonate. The catalyst used in the third step (step c) in the processis preferably 2-pyridinol. This reaction is non-racemising and providesenantiomerically pure (S)-compounds of formula (8′) in the case wherethe (S) enantiomer of compound (9) is used as starting material.

According to an alternative process, said compound of general formula(6′) of the invention as defined above may be manufactured by a processcomprising the step of cyclisation of the compound of formula (11′),wherein R^(1′) and R^(2′) are as defined above. This process is carriedout according to Scheme 4′. below:

According to a second variant, the compound of formula (6′) ismanufactured by a second process comprising the following steps:(a) reaction of an α-ketocarboxylic acid derivative of formula (12′)

wherein R^(1′) is as defined above with a pyrrolidinone of formula (13′)

wherein R^(2′) is as defined above,(b) reaction of the corresponding compound of formula (14′) thusobtained

wherein R^(1′) and R^(2′) are defined as above, with hydrogen in thepresence of an asymmetric hydrogenation catalyst;(c) isolation of the resulting compound.

This second process has as a major advantage that it is much more rapidand simpler, comprising fewer steps than the first ‘LRC’ route asdiscussed above. All details of this process are disclosed in theapplication PCT/EP01/01956 where it is described for compounds of a moregeneral formula. Said application is hereby further incorporated byreference.

According to a third variant, compounds of the general formula (6′) asdefined above are manufactured by a third new process comprisingfollowing steps:(a) reaction of a compound of formula (15′)

wherein R^(1′) is as noted above and X is Cl, Br, I, alkylsulphonate orsulfate; with a pyrrolidone of general formula (13′)

wherein R^(2′) is as noted as above;(b) reaction of the corresponding compound of formula (16′) thusobtained

with ethyl-X, wherein X is Cl, Br, I, alkylsulphonate or sulfate in thepresence of an asymmetric alkylation catalyst or additive;(c) isolation of the resulting compound of formula (6′).

According to this third variant, R^(1′) is preferably C₃-C₄ alkyl,especially tertbutyl.

This third new process as such for the manufacture of a compound offormula (6′) is another aspect of the present invention.

According to this third process, the asymmetric alkylation catalyst oradditive is preferably a chiral amine, most preferably selected from(S)-1-(2-pyrrolidinylmethyl)-pyrrolidine (17),(R)-2-methoxyethoxyethyl-1-phenyl-2-piperidinoethylamine (18) and(S)-1-methyl-2-anilinomethyl pyrrolidine (19).

Step (b) of this process is preferably performed in the presence of abase (such as mineral, organic or organometallic bases). This base ismost preferably butyllithium.

Especially when R^(1′) is not methyl or ethyl, this third process maycomprise an additional reaction step wherein the compound obtained fromstep (b) is reacted with an alcohol of formula R¹OH wherein R¹ is methylor ethyl, preferably in the presence of an acid, so that a compound offormula (6′) is formed wherein R^(1′) is methyl or ethyl.

This third process has the advantage that it comprises only few reactionsteps. Another advantage is that it may be performed using inexpensiveand readily available raw materials.

According to a fourth variant, the compound of the general formula (6′)as defined above is prepared by a fourth new process comprisingfollowing steps:

(a) reaction of a compound of general formula (20′)

(a) reaction of a compound of general formula (20′)

wherein R^(1′) is as noted above, with a pyrrolidone of general formula(13′)

wherein R^(2′) is defined as above:(b) separation of the corresponding compound of general formula (21′)thus obtained wherein R^(1′) and R^(2′) are defined as above; and

(c) isolation of the resulting compound of general formula (6′).

This fourth new process as such for the manufacture of a compound offormula (6′) is another aspect of the present invention.

According to this fourth process, the compound of the general formula(6′) as defined above is preferably isolated by industrial chiralchromatographic separation (batch, MCC (Multi Column Chromatography) orSMB (simulated moving bed)) of a compound of general formula (21′)according to Scheme 7′. below.

According to this fourth process, (S)-PBE and (S)-PBM can be separatedusing chiral HPLC by means of commercially available chiral stationaryphases. These separations can more particularly be performed usingchromatographic columns sold by DAICEL Company or SHISEIDO Company. Thechromatographic process can be carried out using either the batch or MCCprocess. Each enantiomer can be separated using a chiral stationaryphase to yield enantiomerically pure (S)-PBM and (S)-PBE.

The preferred DAICEL columns such as the columns sold under thetrademark CHIRALPAK AD, CHIRALPAK AS and CHIRALPAK OD were found to beefficient to this end when mobile phases such as mixtures of alkaneswith alcohols were used or even a pure alcohol or mixtures of alcohols.The alkane or mixtures of alkanes particularly referred to are: hexane,isohexane or heptane. The alcohol or mixtures of alcohols particularlyreferred to are: propanol, isopropanol, ethanol or methanol. There is apreference for the use of heptane among the alkanes and there is apreference for the use of ethanol and methanol among the alcohols. Thereis a preference for the following mixtures: 50% to 95% for the alkaneand 50% to 5% for alcohol(s), or 100% of alcohol.

The preferred SHISEIDO columns such as the columns sold under thetrademark CERAMOSPHER CHIRAL RU-2 or CERAMOSPHER CHIRAL RU-1 were foundto be efficient for the separation when alcohols were used as mobilephase. The alcohols referred to are: propanol, isopropanol, ethanol ormethanol. There is a preference for the use of ethanol and methanolamong the alcohols.

The extrapolation of small-scale batch separations of this type to anindustrial scale proceeds without difficulty in either batch orcontinuous mode.

The optimum conditions as determined by chiral HPLC for the separationof both PBE & PBM are presented in Tables I and III below. An estimatedproductivity for PBE and PBM using the MCC process is also given inTables II and IV. TABLE I Examples of separation by chiral HPLC: PBMPhase provider Phase Solvents k′l Alpha Resolution Daicel Chiralpak ® ADEthanol 50%/i-Hexane 50% 0.499 1.19 1.06 Daicel Chiralpak ® AD Ethanol2%/Methanol 8%/Hexane 90% 2.432 1.45 2.1 Daicel Chiralpak ® ADAcetonitrile 100% 0.549 1.3 0.79 Daicel Chiralpak ® AD Ethanol10%/Heptane 90% 3.901 1.24 1.19 Daicel Chiralpak ® AD Ethanol5%/Methanol 5% Heptane 90% 3.646 1.41 1.92 Daicel Chiralpak ® ASi-Propanol 10%/i-Hexane 90% 9.408 1.28 2.6 Daicel Chiralpak ® AS Ethanol10%/i-Hexane 90% 3.035 1.17 1.65 Daicel Chiralpak ® AS Propanol10%/i-Hexane 90% 2.987 1.14 1.34 Daicel Chiralpak ® OD-H Ethanol5%/i-Hexane 95% 2.49 1.23 2.97 Daicel Chiralpak ® OD-H Propanol5%/i-Hexane 95% 1.94 1.22 2.58 Shiseido Ceramospher Chiral RU-1 Methanol100% 4.69 1.28 1.56 Shiseido Ceramospher Chiral RU-2 Methanol 100% 3.7471.29 1.5 Shiseido Ceramospher Chiral RU-2 Ethanol 100% 4.853 1.32 1.19

TABLE II Estimated productivity using MCC process: PBM Phase providerPhase Solvents Productivity (kg/kg/day) Daicel Chiralpak ® AD Ethanol2%/Methanol 8%/i-Hexane 90% 0.17

Productivity as presented in the above table is expressed as Kg ofracemic PBM engaged per Kg of chiral stationary phase per day. TABLE IIIExamples of separation by chiral NPLC: PBE Phase provider Phase Solventsk′l Alpha Resolution Daicel Chiralpak ® AD Ethanol 50%/i-Hexane 50%0.449 1.3 1.15 Daicel Chiralpak ® AD Ethanol 2%/Methanol 8%/Hexane 90%1.955 1.9 3.32 Daicel Chiralpak ® AD Acetonitrile 100% 0.554 1.8 2.05Daicel Chiralpak ® AD Ethanol 10%/Heptane 90% 3.076 1.5 4.4 DaicelChiralpak ® AD Ethanol 5%/Methanol 5% Heptane 90% 2.971 1.7 2.93 DaicelChiralpak ® AD Methanol 5%/Benzine 95% 3.227 1.7 2.99 Daicel Chiralpak ®AD i-Propanol 10%/i-Hexane 90% 5.029 2.16 7.39 Daicel Chiralpak ® ADEthanol 10%/i-Hexane 90% 1.764 1.9 5.97 Daicel Chiralpak ® AD Propanol10%/i-Hexane 90% 1.733 1.86 5.46 Daicel Chiralpak ® AD Ethanol5%/i-Hexane 95% 1.878 1.13 1.66 Daicel Chiralpak ® AD Propanol5%/i-Hexane 95% 1.44 1.14 1.56 Shiseido Ceramospher Chiral Ru-1 Methanol100% 5.047 1.89 3.57 Shiseido Ceramospher Chiral Ru-2 Methanol 100%3.869 1.84 3.21 Shiseido Ceramospher Chiral Ru-2 Ethanol 100% 3.97 2.011.94

TABLE IV Estimated productivity using MCC process: PBE Phase providerPhase Solvents Productivity (kg/kg/day) Daicel Chiralpak ® AD Ethanol10%/Heptane 90% 0.84

Productivity as presented in the above table is expressed as Kg ofracemic PBE engaged per Kg of chiral stationary phase per day.

In the implementation of the processes according to the invention, thereaction products may be isolated from the reaction medium and, ifnecessary, further purified according to methodologies generally knownin the art such as, for example extraction, crystallisation,distillation and chromatography, or any combination of the same.

Stereoisomerically pure forms of said compounds of the invention (andsaid intermediates) can be obtained by the application of proceduresknown to a chemist skilled in the art. For example, diastereoisomers canbe separated by physical methods such as selective crystallisation orchromatographic techniques, e.g. counter current distribution, liquidchromatography and related methods. Enantiomers can be obtained fromracemic mixtures by first converting said racemic mixtures with suitableresolving agents such as, for example, chiral acids, to mixtures ofdiastereolsomeric salts or compounds; then physically separating saidmixtures of diastereoisomeric salts or compounds by, for example,selective crystallisation or chromatographic techniques, e.g. liquidchromatography and related methods; and finally converting saidseparated diastereomeric salts or compounds into the correspondingenantiomers.

Alternatively, pure stereochemically isomeric forms may be obtained byusing enantioselective reactions according to procedures known by theperson skilled in the art.

Another alternative manner of separating the enantiomeric forms of thecompounds of formula (6) or (6′) and intermediates involves liquidchromatography, in particular liquid chromatography using a chiralstationary phase.

According to another aspect, the present invention also relates to anycompounds obtained by a process of the invention as defined above. Inparticular, the invention comprises Levetiracetam obtained by saidprocesses. More particularly, the present invention also relates to newcompounds obtainable by the processes according to the invention such ascompounds of formula (22′) wherein R^(2′) is 2-fluoro-2-methylpropyl orcyclopropylmethyl. More specifically the present invention also relatesto the (4S) and (4R) diastereoisomers of(2S)-2-[4-(2-fluoro-2-methylpropyl)-2-oxo-1-pyirolidinyl]butanamide andof (2S)-2-[4-cyclopropylmethyl)-2-oxo-1-pyrrolidinyl]butanamide, andpharmaceutical compositions containing such compounds and their use aspharmaceuticals.

The following examples serve to illustrate the invention and thereforeshould not be taken to limit the scope thereof.

EXAMPLES Example 1

Step 1-Synthesis of methyl (S)-aminobutyrate hydrochloride

5.0 g of (S)-amino butyric acid (23) was suspended in 50 ml of methanoland stirred at 0-5° C. 6.35 g of thionyl chloride was added dropwiseover 45 min to form a clear solution. After stirring for 20 hours atroom temperature, the reaction was concentrated under reduced pressureto dryness and the almost colourless residue solidified to give therequired product which was dried in an oven at 50° C. under vacuum(7.6g; 102% crude yield). The same reaction was scaled-up from 200 g ofthe amino acid and provided 296 g (99.5% yield) of product (24).

Analysis gave the following results:

1H NMR (DMSO-d₆): d 0.94 (3H, t) 1.88 (2H, q) 3.75 (3H, s) 3,9 (1H, m)8.8 (3H, m).

m.p.: 107° C.-110° C.

IR: 2876 cm⁻¹, 1742 cm⁻¹.

TLC: SiO_(2,) 20 %MeOH/80 %EtOAc/1 %NH₄OH, UV & IR.

(TLC is an abbreviation for thin layer chromatography).

Step 2-Synthesis of methyl (S)-aminobutyrate-N(4-ethylbutyrate)

2.0 g of (S)-aminobutyrate hydrochloride salt (24) was dissolved andstirred at room temperature in 20 ml of 2-propanol, followed by additionof 2.8 g of sodium carbonate and the reaction was then heated to reflux.When reflux temperature was reached, 2.8 g of 4-BBE(ethyl-4-bromobutyrate) was added dropwise over a period of 10 min, withreflux and stirring being maintained for 24 hrs. The reaction medium wasallowed to cool to room temperature, the salts were filtered and rinsedwith 50 ml of 2-propanol. Following this alkylation the desired product(25) may be isolated and purified either by chromatography or via thehydrochloride salt (25′) as depicted in Scheme 10. above and asdescribed in Methods A and B below.

(Method A): The filtrate was concentrated under reduced pressure to give3.0 g of a pale yellow liquid. This liquid was purified bychromatography through 125 g of silica and eluted with a 50/50 mixtureof hexane/ethyl acetate to provide the required 2.45 g (81% yield) monoalkylated ester (25) (Method B): Chromatography can be avoided if thecorresponding hydrochloride salt is generated, precipitated and filteredfrom a mixture of isopropanol and DIPE (di-isopropylether). Treatment ofthis salt (25′) with sodium carbonate in water and extraction with ethylacetate and concentration provides the pure free base (25) (the requiredmono alkylated ester) as a liquid.

Analysis gave the following results:

¹H NMR (CDCl₃):d 0.9 (3H, t) 1.2 (2H, t) 1.4 (1H, s) 1.5-1.7 (4H, m)2.3-2.7 (4H, m) 3.15 (1H, t) 3.7 (3H, s) 4.1 (2H, q).

The identity of the product is confirmed by GC-MS, TLC.

IR:2938 cm⁻¹, 1730 cm⁻¹.

TLC:SiO_(2,) 50%Hexane/50%EtOAc, UV & IR.

Step 3-Synthesis of methyl (S)-pyrrolidino-butyrate (26) [(S)-PBM)]

1.0 g of compound (25) and 2-pyridinol (0.02g; 5 mol %) weremagnetically stirred in 5 ml of toluene at reflux for 24 hrs. Thereaction mixture was allowed to cool to room temperature and TLCanalysis showed almost complete conversion. The reaction mixture wasthen evaporated under reduced pressure to leave crude (S)-PBM (26) as apale brown liquid (1.0 g).

The identity of the product was confirmed by GC-MS, TLC, HPLC (Chiraland Achiral) using external references.

Step 4-Ammonolysis of (S)-PBM to give Levetiracetam.

11.3 g of ammonia gas was condensed in 13.2 ml of water at approximately0° C. and the temperature was maintained at 0-5° C. Then 20 g of (S)-PBM(26) was added dropwise over a period of 10 min and reaction mixture wasmaintained at 5° C. and stirred for minimum 8 hrs (reaction was completeas indicated by TLC). The reaction mixture was then evaporated todryness under vacuum and dried by means of toluene (2×50 ml) to giveminimum 17 g (92%) of crude (S)-pyrrolidinobutyramide (crudeLevetiracetam) as an off-white to beige solid.

Analysis gave the following results (chiral and achiral HPLC): Theextent of racemisation was 0.0%. The extent of hydrolysis was measuredto 2.5%.

Example 2

17.3 g of ammonia gas were condensed in 22 ml of water at 0° C. andtemperature maintained at 0-5° C. Then 20 g of (S)-PBE obtained via SMBseparation of the corresponding racemic mixture were added dropwise overa period of 2 min and the reaction mixture was maintained at 5° C. andstirred for 96 hrs (reaction was complete as judged by TLC). Thereaction mixture was then evaporated to dryness under vacuum and driedby means of toluene (2×100 ml) to give minimum 14.8 g (87%) of crude(S)-pyrrolidinobutyramide as a brown orange solid. Analysis gave thefollowing results (chiral and achiral HPLC): The extent of racemisationwas 1.6% with 6.6% hydrolysis.

Example 3

10.3 g of ammonia gas were condensed in 13.2 ml water at 0° C. and thetemperature of the system was maintained at 0-5° C. 20 g of (S)-PBEobtained via asymmetric hydrogenation was then added dropwise over aperiod of 10 min, maintaining the reaction mixture at 5° C. The systemwas then stirred for 96 hrs, with TLC indicating completion of reaction.The reaction mixture was then evaporated to dryness under vacuum anddried by means of toluene (2×50 ml) to give minimum 15.7 g (92%) ofcrude (S)-pyrrolidinobutyramide as a brown orange solid. Analyses gavethe following results (chiral and achiral HPLC): The extent ofracemisation was 0.2% with 3.4% hydrolysis.

Example 4

A reaction flask was charged with the chiral amine (34) (1.07 equivalent(eq.); and anhydrous toluene (15 vol) with stirring under an inertatmosphere. The solution was cooled below −70° C. and BuLi (2.5 M inhexane, 1.04 eq.) was added dropwise. The reaction mixture was stirredfor 30 min at this temperature, then at −10° to 0° C. for 10 min. Asolution of t-butyl 2-(2-oxopyrrolidin-1-yl)-acetate (32) (600 mg, 1eq., 1 wt) in toluene (5 vol) was added slowly, keeping the reactiontemperature below −70° C. The reaction mixture was stirred at −40 to−50° C. for 30 min. Ethyl iodide 2.5 eq., 1 vol) was then added and thereaction mixture was stirred at −50 to −40° C. for 3 hrs. After beingkept in the freezer at approximately −40° C. overnight, the reactionmixture was diluted with pH 7 buffer (KH₂PO₄/KOH, 1 M, 33 vol) anddichloromethane (33 vol). The aqueous phase was extracted withdichloromethane (3×16 vol) and the combined organic extracts were thendried over MgSO₄ and concentrated in vacuo to give crude material.Purification of this crude product using flash chromatography (SiO₂, 40wt) with hexane/EtOAc eluent gave the desired alkylated product (33) in78% yield.

1H-NMR in CDCl₃: δ0.85t(3H), 1,4s(9H), 1.5-1.7 m(1H), 1.9-2.0 m(3H),2.45 m(2H), 3.25 m (1H), 3.5 m(1H), 4.5 dd(1H)

HPLC analysis: t-Butyl 2-(2-oxopyrrolidin-1-yl)-butanoate (25 mg) wasaccurately weighed into a 25 ml volumetric flask. Mobile phase (99:1hexane/isopropanol, 20 ml,) was added and the sample was dissolved usingultrasonication. After cooling to ambient temperature the concentrationwas adjusted with mobile phase to give a working concentration of 1mg/ml. The analysis was conducted using a column sold under thetrademark CHIRACEL OD (4.6×250 mm, DAICEL), flow rate of 1 ml/min, UVdetection at 250 nm and injection volume of 20 μl at ambienttemperature. The relative retention times of the two enantiomers was17.9 and 22.3 minutes

TLC conditions: SiO₂ in EtOAc; visualisation with KMnO₄.

Example 5

1. Evaluation of type of solvent most suitable for ammonolysis of(S)-PBE.

The ammonolysis of (S)-PBE was investigated in the presence of water,toluene, methanol and ethyl acetate. It was shown that the ammnonolysisof (S)-PBE can only be successfully realized in the presence of water.When using methanol, the reaction is very slow and when using the othersolvents mentioned above the extent of reaction is minimal.

2. Evaluation of optimum reaction temperature for the ammonolysis of(S)-PBE to form Levetiracetam.

The ammonolysis of (S)-PBE was carried out either at room temperature orat 40° C. using (S)-PBE (1 equivalent) in the presence of water (6,5volume) and various concentrations of NH₃ (15, 10, 7, 5, and 2equivalents). The reactions were carried out at room temperature and 40°C., being followed by TLC for at least 24 hours. At the end of thereaction the extent of racemisation and hydrolysis was determined byHPLC.

It was shown that:

-   -   good conversion was obtained, especially when at least 4        equivalents of NH₃ (per eq. of (S)-PBE) were used;    -   the extent of racemisation did not exceed 8% at 40° C. and        decreased with reaction temperature. At temperatures between 0        and 25° C., the extent of racemisation was less than 3%;    -   the amount of hydrolysis was low, especially at higher molar        ratios of NH₃ to (S)-PBE.

3. Evaluation of different concentrations of NH₃ for ammonolysis of(S)-PBE.

Six experiments were performed in a 100 ml reactor while varying theconcentration of NH₃ and reaction temperature. (S)-PBE (1 equivalent)was mixed with 10 equivalents of NH₃ from either a commercial solutionof NH₃ (28% w/w) or a more concentrated solution (±50% w/w). Thetemperatures used were either 5, 10 or 20° C. The reaction was followedby TLC until no (S)-PBE remained and the extent of hydrolysis andracemisation was determined by HPLC.

It was shown that:

-   -   a more concentrated solution of NH₃ did not substantially        influence the extent of racemisation.        -   the extent of racemisation was always less than 3% at all            reaction temperatures which were tested,    -   the extent of racemisation increases only very moderately        between 5 and 20° C.,    -   the extent of hydrolysis was low, especially when using        concentrated NH₃ solution (±50% w/w).    -   the extent of racemisation is always lower at lower reaction        temperature.

In summary, the following conclusions can be made:

-   -   the ammonolysis can easily be performed in the presence of water        (containing preferably at least 4 equivalents of NH₃), this        reaction does not require any catalyst and may be performed in        less than 24 hours.    -   the extent of racemisation is low (less than 3% when reaction        temperature is less than 20° C.), and concentration of NH₃ was        found to have only a minor influence on the racemisation,    -   the extent of hydrolysis can be reduced in an even more        substantial way when using a more concentrated solution of NH₃        (±50% w/w) at low reaction temperature (reaction takes less than        48 hours).

Example 6

(S)-PBE was reacted under the conditions specified in Table VI. Theresults are summarised in Table VI. below. TABLE VI

HPLC Analysis area % Reaction conditions Levetiracetam No (S)-PBE NH₃H₂O Time T° acid or (S)-Amide (R)-Amide Exp. (g.) (eq.) (Vol.) (hrs) (°C.) (% area) (% area) (% area) 6 20 6.2 0.66 96 h 00 5 3.44 97.85 2.00

The starting material contained 1.6% of the (R)-enantiomer and 98.4% ofthe (S)-enantiomer. The difference in enantiomeric purity between thestarting material and the final amides obtained was 0.4%. This resultcorresponds to the degree of racemisation accompanied by saidammonolysis.

The product obtained from the experiment described above wasrecrystallised in eight volumes of acetone and filtered at 2° C. to givethe final product, (S)-(-)-α-ethyl-2-oxo-1-pyrrolidine acetamide orLevetiracetam in 69.1% yield. The recrystallised product contained 0.11%of the (R)-amide product and 0.08% of hydrolysed product.

Example 7

(S)-PBM was reacted under the conditions specified In Table VIII. Theresults are summarised in Table VIII. below. TABLE VIII

HPLC Analysis area % Reaction conditions Levetiracetam Opposite No(S)-PBE NH₃ H₂O Time T° acid (S)-Amide (R)-Amide Exp. (g.) (eq.) (Vol.)(hrs) (° C.) (% area) (% area) (% area) 22 22 6.0 0.66 16 h 40 5 3.6896.31 2.53

The starting material contained 96.3% of the (S)-enantiomer and 3.5% ofthe (R)-enantiomer. The difference in enantiomeric purity between thefinal product Levetiracetam and the starting material (S)-PBM wasapproximately 0.2%, indicating indeed that the amnmonolysis isaccompanied by a negligible racemisation in this case.

The final product obtained from the experiment above was recrystallizedfrom eight volumes of acetone and filtered at 4° C. Levetiracetam isobtained in 73.3% yield. The recrystallized product contained 1.64% ofthe opposite enantiomeric amide and 0.03% of the hydrolysed product.Recrystallisation in the presence of acetone as described allowsproduction of Levetiracetam of a sufficient quality for commercialpurposes.

The same reaction was finally performed on an increased scale accordingto Scheme 18. below. Racemisation was as previously observed negligible(0.2%) .

In summary, it has been shown that Levetiracetam may be obtained viaammonolysis of (S)-PBE in concentrated NH₃ (50% in water) and at 5° C.Scaling-up of this reaction has been successfully demonstrated in 0.6volumes of water in the presence of 6 equivalents of NH_(3.) The extentof racemisation varies between 0.4 and 2.0%, that of hydrolysis between3.5 and 6.6%, with a reaction time of approximately 96 hours.

Alternatively, Levetiracetam may equally be obtained via ammonolysis of(S)-PBM in 0.6 volumes of water containing 6 equivalents of NH₃ and at5° C. The reaction time is much shorter and can be realised in 8 to 10hours. The extent of racemisation varies between 0.0 and 0.2% and thatof hydrolysis ranges from 1.8 to 3.6%.

Example 8

8.1 Preparation of methyl(2S)-2-[2-oxo-(4S)-4-propyl-1-pyrrolidinyl]butanoate

A reaction flask was charged with 2 g of methyl(Z)-2-[2-oxo-(4S)-4-propyl-1-pyrrolidinyl]-2-butenoate, 20 ml ofanhydrous and degassed methanol and 27 mg of (S,S)-Me-DUPHOS/Rh(BF₄).The reaction flask was purged with hydrogen and the hydrogen pressurewas adjusted to 10 atm. This reaction mixture was stirred during about20 hours at room temperature and then concentrated. 1.96 g of methyl(2S)-2-[2-oxo-(4S)-4-propyl-1-pyrrolidinyl]butanoate was obtained.

8.2 Ammonolysis

Ammonia gas was condensed in 2 ml water at 0-5° C. and the temperatureof the system was maintained at 0-5° C. 0.68 g of methyl(2S)-2-[2-oxo-(4S)-4-propyl-1-pyrrolidinyl]butanoate obtained such asdescribed above was then added dropwise, maintaining the reactionmixture at 0-5° C. The system was then stirred for 6 hrs, with TLCindicating completion of reaction. After standing overnight at ambienttemperature the reaction mixture was concentrated at 40° C. under vacuumand further dried by azyeotropic distillation with toluene to give 150mg of crude (2S)-2-[2-oxo-(4S)-4-propyl-1-pyrrolidinyl]butanamide.

1. A compound of formula (6)

wherein R¹ is methyl or ethyl; and R² is C₂-C₄ alkyl, C₂-C₄ alkenyl orC₂-C₄ alkynyl, optionally substituted by one or more halogen; as well asthe stereoisomers and mixtures thereof.
 2. The compound according toclaim 1, wherein the R² substituent is present at position 4 on the ringstructure, according to the following general formula (7).


3. The compound according to claim 2, wherein R¹ is methyl and R² ispropyl or 2,2-difluorovinyl.
 4. The compound according to claim 2,wherein R¹ is ethyl and R² is propyl or 2,2-difluorovinyl.
 5. Thecompound according to claim 2, wherein R¹ is methyl and R² is asubstituent selected from 2-fluoro-2-methylpropyl, 2,2-difluoropropyl,cyclopropylmethyl and 2,2,2-trifluoroethyl.
 6. The compound according toclaim 2, wherein R¹ is ethyl and R² is a substituent selected from2-fluoro-2-methylpropyl, 2,2-difluoropropyl, cyclopropylmethyl and2,2,2-trifluoroethyl.
 7. The compound according to claim 1, which is anS isomer, according to the following formula (8)


8. A process for the manufacture of a compound according to claim 1,said process comprising following steps: (a) reaction of a compound offormula (9)

with an alcohol of formula R¹OH wherein R¹ is as noted in claim 1, (b)reaction of the corresponding compound of formula (10) thus obtained

with a R²-substituted-ethyl-4-bromobutyrate wherein R² is as noted inclaim 1, (c) cyclisation of the corresponding compound of formula (11)thus obtained

with a catalyst, (d) isolation of the resulting compound.
 9. The processaccording to claim 8, wherein step (a) is performed in the presence ofthionyl chloride and an alcohol.
 10. The process according to claim 8,wherein step (b) is performed in the presence of a base and an alcohol.11. The process according to claim 8, wherein the catalyst used in step(c) is pyridinol.
 12. The process for the manufacture of a compoundaccording to claim 1, said process comprising a step of cyclisation ofthe compound of the formula (11)

wherein R¹ and R² are as in claim
 1. 13. A process for the manufactureof a compound according to claim 1, said process comprising followingsteps: (a) reaction of an α-ketocarboxylic acid derivative of formula(12)

wherein R¹ is as noted in claim 1, with a pyrrolidinone of formula (13)

wherein R² is as noted in claim 1, (b) reaction of the correspondingcompound of formula (14) thus obtained

with hydrogen in the presence of an asymmetric hydrogenation catalyst,and (c ) isolation of the resulting compound.
 14. A process for themanufacture of a compound according to claim 1, said process comprisingfollowing steps: (a) reaction of a compound of formula (15)

wherein R^(1′) is C₁-C₆ alkyl and X is Cl, Br, I, alkylsulphonate orsulfate; with a pyrrolidone of formula (13)

wherein R² is as in claim 1; (b) reaction of the corresponding compoundof formula (16) thus obtained

with ethyl-X, wherein X is Cl, Br, I, alkylsulphonate or sulfate in thepresence of an asymmetric alkylation catalyst or additive; (c)optionally, when R^(1′) is different from R¹, reaction of the compoundobtained in step (b) with an alcohol of formula R¹ OH, and (d) isolationof the resulting compound of formula (6).
 15. A process for themanufacture of a compound according to claim 1, said process comprisingfollowing steps: (a) reaction of a compound of general formula (20)

wherein R¹ is as defined in claim 1, with a pyrrolidone of generalformula (13)

wherein R² is defined as in claim 1; (b) separation of the correspondingcompound of formula (21) thus obtained

wherein R¹ and R² are defined as in claim 1; (c) isolation of theresulting compound of formula (6).
 16. A process for the manufacture ofa compound of formula (22′)

wherein R^(2′) is hydrogen, C₁-C₄ alkyl, C₂-C₄ alkenyl or C₂-C₄ alkynyl,optionally substituted by one or more halogen, said process comprisingthe ammonolysis of the corresponding compound of formula (6′)

wherein R^(1′) is C₁-C₆ alkyl and R^(2′) is hydrogen, C₁-C₄ alkyl, C₂-C₄alkenyl or C₂-C₄ alkynyl, optionally substituted by one or more halogen,in the presence of water.
 17. The process according to claim 16, whereinsaid ammonolysis is performed in a mixture of water and an alcohol. 18.The process according claim 16, wherein said ammonolysis is performed ina 30-80% (w/w) NH₃ solution in water.
 19. The process according to claim16, wherein said ammonolysis is performed at 0 to 25° C.
 20. The processaccording to claim 16, wherein the molar ratio of NH₃ to the compound offormula (6′) is at least
 4. 21. The process according to claim 16,wherein a compound of formula (6′) is used wherein R^(1′) is methyl andR^(2′) is hydrogen.
 22. The process according to claim 16, wherein acompound of formula (6′) is used wherein R^(1′) is ethyl and R^(2′) ishydrogen.
 23. The process according to claim 16, wherein a compound offormula (6′) is used wherein the R^(2′) substituent is present atposition 4 on the ring structure, according to the following generalformula (7′)


24. The process according to claim 16, wherein a compound of formula(6′) or (7′) is used wherein R^(2′) is selected from the group ofpropyl, 2,2-difluorovinyl, 2-fluoro-2-methylpropyl, 2,2-difluoropropyl,cyclopropylmethyl and 2,2,2-trifluoroethyl.
 25. The process according toclaim 16, wherein compound (6′) is an S isomer according to thefollowing formula (8′)


26. The process according to claim 16, wherein compound (6′) is obtainedby a process comprising following steps: (a) reaction of a compound offormula (9)

with an alcohol of formula R^(1′)OH wherein R^(1′) is as noted in claim16, (b) reaction of the corresponding compound of formula (10′) thusobtained

with a R^(2′)-substituted-ethyl-4-bromobutyrate wherein R^(2′) is asnoted in claim 16, (c) cyclisation of the corresponding compound offormula (11′) thus obtained

in the presence of a catalyst, and (d) isolation of the resultingcompound.
 27. The process according to claim 16, wherein compound (6′)is obtained by a process comprising a step of cyclisation of a compoundof formula (11′)

wherein R^(1′) and R^(2′) are as noted in claim
 16. 28. The processaccording to claim 16, wherein compound (6′) is obtained by a processcomprising following steps: (a) reaction of an α-ketocarboxylic acidderivative of formula (12′)

wherein R^(1′) is as noted in claim 16, with a pyrrolidinone of formula(13′)

wherein R^(2′) is as noted in claim 16, (b) reaction of thecorresponding compound of formula (14′) thus obtained

with hydrogen in the presence of an asymmetric hydrogenation catalyst,and (c) isolation of the resulting compound.
 29. The process accordingto claim 16, wherein compound (6′) is obtained by a process comprisingfollowing steps: (a) reaction of a compound of formula (15′)

wherein R^(1′) is as noted in claim 16 and X is Cl, Br, I,alkylsulphonate or sulfate; with a pyrrolidone of formula (13′)

wherein R^(2′) is as in claim 16, (b) reaction of the correspondingcompound of formula (16′) thus obtained

with ethyl-X, wherein X is Cl, Br, I, alkylsulphonate or sulfate in thepresence of an asymmetric alkylation catalyst or additive, (c) isolationof the resulting compound.
 30. The process according to claim 16,wherein compound (6′) is obtained by a process comprising followingsteps: (a) reaction of a compound of general formula (20′)

wherein R^(1′) is as noted in claim 16, with a pyrrolidone of generalformula (13′)

wherein R^(2′) is defined as in claim 16, (b) separation of thecorresponding compound of formula (21′) thus obtained, and

(c) isolation of the resulting compound of formula (6′).